Benzodiazepine (BZP) compounds, such as diazepam which is a representative compound, have anxiolytic activity and hence have been developed as anxiolytic drugs, but they have also anticonvulsant, sedative and hypnotic activities and hence these compounds have been used in wide clinical fields such as (1) anxiolytic drug, (2) sedative (hypnotic) drug, (3) muscular relaxant, and (4) antiepileptic drug.
BZP compounds have mainly the pharmacological activities such as (1) acclimating activity, (2) hypnotic activity, (3) central muscle relaxant activity, (4) anti-convulsant activity. It is understood that these activities are not exhibited by independent mechanism separately, but are induced by closely related neuropharmacological mechanisms.
Since late 1970s, with progress of pharmacological investigation of BZP compounds, there have been found two footings for clarifying the mechanism of exhibiting the activities thereof, one being a phenomenon of increasing .gamma.-aminobutyric acid agonistic (GABAergic) neurotransmittant mechanism of the central nervous system by the BZP drugs, and another being new finding of BZP specific binding site (BZP receptor) and proving of a mechanism of the functional connection between the brain BZP receptor and GABA receptor. As the result of such investigation, it has almost been established that the GABAergic neurotransmittant mechanism participates in the pharmacological activities of BZP compounds.
Administration of BZP compounds induces side effects such as ataxia, hypnosis, muscle relaxation or lowering of ability of cognition or reflex movement and further formation of resistance and dependence to the drugs, and hence, there are many problems to be improved in the BZP compounds. Studies have been made on non-BZP compounds which have a different chemical structure from BZP compounds but have similar functions in the activation mechanisms. Those compounds including such non-BZP compounds are called as benzodiazepine receptor agonistic drugs. As the non-BZP compounds, there are known, for example, the compounds having the chemical formulae (A), (B) and (C) as shown below.
The compounds having the formulae (A) and (B) are disclosed in Journal of Medicinal Chemistry, vol. 34, p. 2060 (1991). ##STR2##
wherein R.sub.a is a hydrogen atom, R.sub.b -R.sub.d are a methyl group, etc., and R.sub.e is a methoxy group, etc.
The compounds of the formula (C) are disclosed in EP-A2-0588500. ##STR3##
wherein Het is an oxadiazolyl group, R.sup.1 is a benzyl group, etc. and R.sup.2 is a methoxy group, etc.
However, with progress of investigation, there has been found a certain compound among the non-BZP compounds, which has similar high selective affinity to the benzodiazepine (BZP) receptor but has entirely inverse activities [Braestrup, C. et al., Neuropharmacol., 22, pp.1451-1457 (1983)]. When these compounds are administered, they exhibit pharmacological activities such as convulsion increasing activity, anxiety inducing activity, muscle hypertonia. Accordingly, the old BZP compounds which have hitherto been used as anxiolytic drugs are defined as an agonist, and the compounds having thus inverse activities are defined as an inverse agonist.
Since these inverse agonists have been found, intensive studies have been done on the correlation between the modifying (binding) manner and the pharmacological activities of the compounds which bind (exhibit affinity) to the BZP receptor. According to these studies, it has been found that the BZP receptor is present between the GABA receptor (an depressive neurotransmittant) and a chloride ion channel and is a molecular unit to form a complex. The GABA receptor includes an ion channel type GABA.sub.A receptor and a metabolism controlling type GABA.sub.B receptor, and the GABA.sub.A receptor forms a complex with a BZP receptor and the Cl ion channel. The compounds to be bound to the BZP receptor are now classified into an agonist (further subsequently classified into a full agonist and a partial agonist), an inverse agonist (further subsequently classified into a full inverse agonist and a partial inverse agonist) and an antagonist.
The agonist binds selectively to the BZP compounds and thereby acts increasing coupling of the GABA receptor and the Cl ion channel and increases flowing of Cl ion into cells owing to increase of open-close frequency of the Cl ion channel and then stimulates the cell activities owing to decrease of negative electric charge (increases cell stimulation). It is said that the antagonist does not change the coupling function thereof but inhibits binding of the agonist or inverse agonist to the BZP receptor.
There are many method for checking the manner of binding of the compounds to the benzodiazepine receptor, and one of the known methods is a TBPS binding assay. As mentioned here in before, the GABA.sub.A receptor forms a complex with a BZP compound receptor and the Cl ion channel, and it is known that a neurosteroid receptor is present on the GABA.sub.A receptor membrane and a TBPS(t-butylbicyclophosphonothionate) bond recognizing site is located around the Cl ion channel. The function of GABA to the nervous system is modified and controlled by controlling of the opening of the Cl ion channel and transmission of Cl ion into cells within the GABA.sub.A receptor complex molecule under complicated mutual effects. By checking many drugs which act directly or indirectly on the function of the GABA.sub.A receptor complex, it is known that there is a good inverse correlation between the test data of TBSP binding and the test data of Cl ion uptake into cells. For instance, the uptake of Cl ion into cells is decreased by GABA.sub.A receptor agonists (e.g. Muscimol), neurosteroid receptor agonists, diazepam which is the representative benzodiazepaine receptor agonist, or chlonazepam which is a partial agonist, and is increased by benzodiazepine receptor inverse agonist [e.g. DMCM (methyl-6,7-dimethoxy-4-ethyl-.beta.-carboline-3-carboxylate)] and a partial inverse agonist [e.g. FG7142 (N-methyl-.beta.-carboline-3-carboxamide)]. Accordingly, the TBPS binding assay is useful for clarifying the GABA.sub.A receptor function, the in vitro biochemical screening of the drugs acting via allosteric binding site of bezodiazepine drugs, GABA.sub.A receptor complex, etc., and the acting mechanisms of the drugs.
Most of the old BZP compounds such as the compounds of the formulae (A), (B) and (C) have agonistic properties. On the contrary, some compounds having inverse agonistic properties are known, for example, the compounds of the following formulae (D) and (E) (DMCM and FG7142): ##STR4##
The DMCM and FG7142 are disclosed in Colin R. Gardner, Drugs of the Future, vol. 14, pp. 51-67 (1987).
In addition, many investigations have also been made on the correlation between the binding manner to the benzodiazepine receptor and the pharmacological activities of the compounds. As mentioned above, the BZP agonists have been used as anxiolytic drug, hypnotic disorder curing agent (sleep inducing drug) or antiepileptic drug, but it is known that in addition to these activities, they have also an amnestic activity in animals including also human being. Accordingly, BZP inverse agonists are expected to have activities inverse to the amnesia inducing activity, that is, anti-amnestic activity, psychoanaleptic activity. Moreover, it is known that the activity of acetylcholine, which has an important relation to cognition function, is decreased by the BZP agonists and is increased by the BZP inverse agonists, and hence the BZP inverse agonists are expected to exhibit cognition enhancing activity. Thus, it has been expected that the BZP inverse agonists may be useful as psychoanaleptic drug and a drug for treating dysmnesia in senile dementia, cerebrovascular and Alzheimer's dementia.
There is no report as to the compounds of the present invention which have the formula (I) described hereinafter and have high selective affinity to a benzodiazepine receptor and particularly acts as a BZP inverse agonist.